Increased microbial translocation in ME/CFS

"The cause of ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome] is unknown, but gut dysbiosis could be contributing to some of the symptoms and their severity. Developing therapeutic interventions aimed at reducing local inflammation, restoring gastrointestinal tract immunity and integrity and modifying the intestinal microbiome may ameliorate ME/CFS symptoms in a number of affected patients."

Those were the important conclusions reported by Ludovic Giloteaux and colleagues [1] (open-access) who "profiled gut microbial diversity by sequencing 16S ribosomal ribonucleic acid (rRNA) genes from stool as well as inflammatory markers from serum for cases (n = 48) and controls (n = 39)." Authors recount how all 'cases' (participants) fitted the "Fukuda diagnostic criteria" for CFS/ME but "most, perhaps all, also fit the description of SEID [Systemic Exertion Intolerance Disease]." We're also told that a majority of participants with ME/CFS "self-reported gastrointestinal disturbances such as constipation, diarrhea, or intestinal discomfort" something perhaps not unfamiliar to the peer-reviewed research domain (see here).

Looking at inflammatory markers as well as the composition and diversity of those trillions of wee beasties that call us home (the gut microbiome), Giloteaux et al reported some important differences between their groups that might even be considered 'diagnostic' at some point in the future (emphasis on 'some point'). "[The] gastrointestinal tract of ME/CFS  patients is a pro-inflammatory environment" is another of their observations; indeed, based on the idea that: "Abnormal immune activation can be caused by translocation of microbes from an inflamed gut" and reporting elevations in some of the blood markers potentially pertinent to this process. Said microbial translocation (MT) was evidenced by: "(i) significantly raised levels of plasma LPS [lipopolysaccharide] and (ii) significantly higher levels of sCD14 [soluble CD14] and LBP [LPS-binding protein], as indicators of direct LPS stimulation." Interestingly however: "Levels of hsCRP [high-sensitivity C-reactive protein] were higher in the ME/CFS population in comparison to healthy controls... but the difference was not statistically significant."

Examination of stool samples from study participants also found some potentially important differences between the groups as "less diversity as well as increases in specific species often reported to be pro-inflammatory species and reduction in species frequently described as anti-inflammatory" were found in the ME/CFS group. Of particular note were "lower levels of the genus Faecalibacterium, a member of the Ruminococcaceae in the ME/CFS population" and that "Proteobacteria were more abundant in ME/CFS patients than in controls." Minus any sweeping generalisations, such combined findings have been reported in cases of inflammatory bowel disease (IBD) among other things. Utilising a machine-learning approach (something we've seen before on this blog) authors were also "mostly successfully classified into healthy and ME/CFS groups" on the basis of the inflammatory and microbiome data with a little more investigation required.

This is of course not the first time that the gut microbiome has been 'implicated' in cases of ME/CFS (see here). The application of the 'yuck factor 10' that is the faecal microbiota transplantation as one effort to alter the gut microbiome in cases of ME/CFS has also been mentioned too (see here). These latest results add to the interest and indeed, the idea that the gut might be a central organ of either cause or effect when it comes to at least some cases of ME/CFS (see here and see here). But I might also add there is more to do in this area. Giloteaux et al talk a lot about gut barrier integrity as being implicated but didn't directly measure permeability or by how much...

Finally, I do think due credit should be given to some of the research pioneers upon which the Giloteaux findings are based. I'm thinking specifically of Michael Maes of NIOF fame (see here) who has been quite consistently talking about "increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation" in cases of CFS/ME and importantly, what could be potentially done about it [2]. It appears that replicative science might indeed be on his, and his research teams', side. And he just keeps going (see picture).

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[1] Giloteaux L. et al. Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome. 2016; 4: 30.

[2] Maes M. & Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008 Dec;29(6):902-10.

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Giloteaux L, Goodrich JK, Walters WA, Levine SM, Ley RE, & Hanson MR (2016). Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome. Microbiome, 4 (1) PMID: 27338587

What exercise might do to the gut microbiome and gut permeability in CFS/ME

"These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome] patients that may account for the profound post-exertional malaise experienced by ME/CFS patients."

That was the conclusion reached by Sanjay Shukla and colleagues [1] (open-access available here) who analysed the "microbiomes of blood and stool samples" for a small group of "clinically characterized ME/CFS patients" (n=10) and ten matched asymptomatic controls undertaking an exercise test ("a maximal exercise test on an electronically braked cycle ergometer"). Clinically characterised by the way, refers to a diagnosis of CFS using the 1994 CDC case definition.

Blood and stool samples were provided by participants at various time points including baseline, 15 minutes and some days following the exercise test. Indeed we are told that: "Stool samples were collected at baseline (pre-exercise) and 48 and 72 hours post-exercise" which is certainly quite a feat getting 20 people to er, poo(p) on demand on such a timescale.

Analyses of samples and importantly, the state of participants following the exercise test, yielded some potentially interesting results. So: "Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial phyla/genera in ME/CFS patients from baseline to 72 hours post-exercise compared to only 2 of the 9 phyla/genera in controls." The authors interpret this as meaning that bacterial load in those with ME/CFS may be "preferentially enhanced during post-exertional malaise." This was to some degree complemented by blood results "with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls." Again the authors tentatively interpret this as meaning that "bacteria may have translocated into the blood stream from the gut after the maximal exercise challenge" and hence there may be a preferential role for intestinal dysbiosis and altered intestinal permeability in relation to at least some cases of CFS/ME.

These are interesting if preliminary findings. I've previously touched upon the idea that the gut microbiome might be a research target for CFS/ME before on this blog (see here). Allied to the idea that altered intestinal permeability (a.k.a the leaky gut - yes it is a real thing) might also be a feature of 'some' CFS/ME (see here) and one has some intriguing potential investigations to be done alongside the notion that new therapeutic targets could be on the horizon. I say this acknowledging again the small participant group included for study in the Shukla study.

I must also pay further attention to the exercise element of the Shukla paper. Exercise and post-extertional fatigue/malaise is a core feature of CFS/ME (even SEID) and has been the topic of quite a lot of discussion and even arguments when it comes to certain 'therapeutic' options put forward in recent years. Other studies looking more generally at the effects of vigorous exercise on measures of intestinal permeability have suggested that there may be some important physiological changes associated with undertaking a strenuous workout [2]. A specific measure of intestinal permeability is not reported by Shukla and colleagues on this occasion but one wonders whether there may be some important further research to do in this area particularly when one notices the lack of statistical difference in various physiological measures between the ME/CFS participants and controls on this [preliminary] research occasion (see here)?

To close, remembering Alan Rickman...

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[1] Shukla SK. et al. Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). PLoS One. 2015 Dec 18;10(12):e0145453.

[2] Pals KL. et al. Effect of running intensity on intestinal permeability. J Appl Physiol (1985). 1997 Feb;82(2):571-6.

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Shukla SK, Cook D, Meyer J, Vernon SD, Le T, Clevidence D, Robertson CE, Schrodi SJ, Yale S, & Frank DN (2015). Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). PloS one, 10 (12) PMID: 26683192

Abdominal discomfort syndrome in a subset of ME/CFS

"The findings show that ADS [abdominal discomfort syndrome] is a characteristic of a subset of patients with ME/CFS [Myalgic Encephalomyelitis / Chronic Fatigue Syndrome] and that increased bacterial translocation (leaky gut) is associated with ADS symptoms."

Right there. God does not build in straight lines.

So said the study by Michael Maes and colleagues [1] looking at both gastrointestinal (GI) symptom presentation in diagnosed cases of ME/CFS and "the IgA and IgM responses directed against commensal bacteria" - rough translation: an immune system response against some of those microscopic beasties that call us home (residing in our deepest, darkest recesses). Leaky gut by the way, is something that I'm particularly interested in on this blog for quite a few different reasons (see here) and refers to potential issues with the barrier separating the contents of our GI tract from the wider body and the ever-vigilant immune system. Dysfunction of said barrier might mean that an immune response against bacteria are more likely as per a certain Sutterella finding in autism research a few years back. And before you ask, yes, leaky gut is a real concept despite some who would say otherwise...

The term 'abdominal discomfort syndrome' akin, I think, to something around irritable bowel syndrome based on the results of the cluster analysis "performed on gastro-intestinal symptoms" by Maes et al, is an interesting finding. It is not necessarily new news that there may be sub-groups of people described under the label of ME/CFS, one of which might be a 'gut related subgroup' (see here). Indeed, gut inflammation has been mentioned on more than one occasion [2] with something of a connection to the presentation of more functional bowel issues.

What is perhaps novel about the Maes findings is the authors' assertion that their study results point to: "a pathway phenotype, i.e bacterial translocation, that is related to ME/CFS and ADS/IBS and that may drive systemic inflammatory processes." This comes on the back of other evidence suggesting that issues with gut permeability associated with the process of bacterial translocation may be present in cases of ME/CFS and potentially amenable to intervention [3] (although I hasten to add that further research is required on this topic).

Michael Maes is quite a prolific peer-reviewed author when it comes to ME/CFS tapping into some really, really interesting areas of research such as mitochondrial dysfunction [4], oxidative stress [5] and autoimmunity [6]. This latest research venture adds further to the notion that genetics and biology are the drivers of quite a large proportion of cases covered under the umbrella term 'overlapping fatigue syndromes' [7].

And then some music. How about Yellow from Coldplay?

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[1] Maes M. et al. Evidence for the existence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with and without abdominal discomfort (irritable bowel) syndrome. Neuro Endocrinol Lett. 2014 Nov 2;35(6):445-453.

[2] Lakhan SE. & Kirchgessner A. Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond). 2010 Oct 12;7:79.

[3] Maes M. et al. Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome. Neuro Endocrinol Lett. 2007 Dec;28(6):739-44.

[4] Morris G. & Maes M. Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab Brain Dis. 2014 Mar;29(1):19-36.

[5] Morris G. & Maes M. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS). Curr Neuropharmacol. 2014 Mar;12(2):168-85.

[6] Morris G. et al. The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs). Mol Neurobiol. 2014 Apr;49(2):741-56.

[7] Whiteley P. et al. Correlates of Overlapping Fatigue Syndromes. Journal of Nutritional and Environmental Medicine. 2014; 14: 247-259.

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Maes M, Leunis JC, Geffard M, & Berk M (2014). Evidence for the existence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with and without abdominal discomfort (irritable bowel) syndrome. Neuro endocrinology letters, 35 (6), 445-453 PMID: 25433843

Leaky gut and autism: the story so far

Gut or intestinal hyperpermeability a.k.a leaky gut has been a point of some contention when it comes to a complicated set of conditions like the autisms.

Describing the process and mechanism of disruption to the quite delicate barrier which separates our intestinal contents from the wider environment and functions of the body, mention leaky gut to some people and you'll get some pretty peculiar looks. Allied perhaps unfairly to the realm of complementary and alternative medicine (CAM), leaky gut in some circles has not received great press in its attempts to offer an explanation for lots of different (chronic) conditions including autism.

Rumplestiltskin @ Wikipedia 

With autism specifically in mind, leaky gut seemingly encompasses all the most controversial elements about the condition: (i) involvement of the gastrointestinal (GI) tract, (ii) discussions about its possible link with food and diet (more to come on that), and (iii) other variables including who and from where the message about leaky gut originates from.

That and portraying autism as potentially being more than the sum of just the brain as being involved in the presentation of its behavioural characteristics and you have all the required elements in place to push leaky gut into the nether regions of autism research discussions. 

In this mega-post I'm going to ask that you put any prejudice aside for a short while as I intend to have a close look at the [limited] peer-reviewed and almost peer-reviewed evidence mentioning leaky gut and autism. I'll say now that I'm not going to offer some shining recommendation for leaky gut as being a core part of all cases of autism or even that it is a primary part of presentation; the available evidence does not point to that. Instead I'm going to put forward a view that leaky gut might, just might, be a part of some of the complexity of autism, some autism, and where present might offer some interesting leads into underlying pathology and/or intervention.

What is leaky gut?

OK, I should have probably mentioned this before but the name leaky gut is a bit of a misnomer when it comes to describing what might be going on in our deepest, darkest recesses. Everyone has some degree of leaky gut or gut permeability; if not, how would we be able to absorb nutrients from food for example. It's perhaps more pertinent to talk about excess gut permeability or gut hyperpermeability as describing the scenario more accurately.

The basic tenet of leaky gut, sorry gut hyperpermeability, is that the normally 'fairly porous to a certain degree' gut barrier is for whatever reason more permeable and porous than it should be and as a result various 'chemicals' (yep the misuse of that word again) and other material including bacteria and friends, are able to make a journey into the gut membrane and perhaps beyond.

OK so what's the problem with that I hear you ask? Well, the gut barrier is there for a reason and part of that reason is so that our immune system for example, does not get to meet certain biochemicals and bacteria in certain places of the body and do what it is designed to do, mount an immune response against them as part of its protection duties. Think bacterial translocation* - gut bacteria appearing in places other than the gut - as one example. Actually the immune system is only part of the proposed issue here which anyone who has an interest in autism research history and the opioid-excess theory** will know and the suggestion that dietary peptides are able to traverse this barrier and in some shape or form activate opiate receptors. Speculation at least; but if you read my training post on coeliac (celiac) disease, you'll know that gluten peptides can move into at least one part of the gut barrier for whatever reason.

Leaky gut and medicine
Taking aspirin affects the permeability of the gut. No really, it's true as per papers like this one***. Drinking alcohol affects gut permeability too****. What these and other papers demonstrate is that gut permeability is a dynamic process which is very much affected by environmental conditions such as what medicines we take and what we eat and drink. Would you believe me if I told you that taking something like melatonin might also affect gut permeability too (at least in rats)? Albeit in the opposite direction from aspirin and alcohol.

It's also been known for quite a few years that various conditions manifest issues with gut permeability as per the example of the inflammatory bowel diseases (IBDs)***** (open-access). Indeed, various other conditions with an autoimmune element to them have been a real point of discussion with gut hyperpermeability in mind, as per the chatter about type 1 diabetes****** for example.

I'm going to come on to autism shortly, but various other suggestions have been made linking leaky gut to disease and ill-health. One of them - Chronic Fatigue Syndrome (CFS) - has been talked about a few times with this permeability issue in mind on other blogs I'm linked to (see here). Indeed the name Dr Michael Maes carries quite an impressive array of articles on leaky gut and bacterial translocation in relation to all manner of conditions and indeed, some clues as to what intervention might also be able to do*******.

Leaky gut and autism
To save me typing the whole thing out again, I've talked about leaky gut and autism previously on another site (see here). The gist of that article detailed the main papers making up the autism and leaky gut scene to date: D'Eufemia and colleagues******** and their initial intestinal permeability results, Robertson and colleagues********* saying not so fast albeit including participants who were on dietary intervention and de Magistris and colleagues********** (see full-text here) who agreeing with D'Eufemia also suggested that gut permeability might be influenced by the use of a gluten- and casein-free (GFCF) diet so potentially also answering the whys of the Robertson findings.

There is also the conference presentation by Paul Patterson and colleagues (see here) on leaky gut in his offspring mouse model of maternal immune activation (which itself has seen some research action lately) but let's wait until that sees the peer-reviewed light of day. Oh and we have the next installment from de Magistris and colleagues (see here) which will have a post of its own soon [hint: leaky gut remains present in some people on the autism spectrum].

As per my introducing leaky gut with autoimmunity in mind, you might also be able to see how gut permeability issues could potentially be present in cases of autism which also include autoimmune comorbidity for example. So IBDs for example (see here) or coeliac disease (see here) or even type 1 diabetes (see here) might all elevate risk of abnormal gut permeability if present.

Based on this accumulated work alongside other speculations as a function of things like immune reactivity to gluten peptides for example (see here) there is a favourable base to gut hyperpermeability being a feature of autism in anything up to a third of cases. Indeed, outside of the direct measurement of gut permeability, other papers have also mentioned leaky gut in their text; for example as an explanation for those antibodies to Sutterella bacteria found in some cases of autism (see here).

More to see
I've not specifically mentioned about how one goes about assessing gut permeability because that in itself offers a number of potential routes worthy of a post of its own (lactulose:mannitol, PEG, etc.). Nor have I talked about where permeability is greatest in the gut in relation to autism or the issue of what type of permeability might exist (transcellular vs. paracellular). And as for other potential players in gut permeability such as [general] zonulin (see here) and the continuing saga of whether dietary intervention might 'affect' permeability*********** (no medical advice given or intended) or indeed other interventions .... we wait to see what future research offers about these factors specifically with autism in mind.

So after all that, still think leaky gut in autism is a load of old tosh?

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* Berg RD. Bacterial translocation from the gastrointestinal tract. Adv Exp Med Biol. 1999;473:11-30.

** Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

*** Lambert GP. et al. Effect of aspirin dose on gastrointestinal permeability. Int J Sports Med. 2012 Jun;33(6):421-5. doi: 10.1055/s-0032-1301892.

**** Worthington BS. et al. Effect of daily ethanol ingestion on intestinal permeability to macromolecules. Am J Dig Dis. 1978; 23: 23-32.

***** Gerova VA. et al. Increased intestinal permeability in inflammatory bowel diseases assessed by iohexol test. World J Gastroenterol. 2011 May 7; 17(17): 2211–2215.

****** Vaarala O. Leaking gut in type 1 diabetes. Curr Opin Gastroenterol. 2008 Nov;24(6):701-6. doi: 10.1097/MOG.0b013e32830e6d98.

******* Maes M. & Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008 Dec;29(6):902-10.

******** D'Eufemia P. et al. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996 Sep;85(9):1076-9.

********* Robertson MA. et al. Intestinal permeability and glucagon-like peptide-2 in children with autism: a controlled pilot study. J Autism Dev Disord. 2008 Jul;38(6):1066-71. doi: 10.1007/s10803-007-0482-1.

********** de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24. doi: 10.1097/MPG.0b013e3181dcc4a5.

*********** Sildorf SM. et al. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Rep. 2012 Jun 21;2012. pii: bcr0220125878. doi: 10.1136/bcr.02.2012.5878.

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de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, De Rosa M, Francavilla R, Riegler G, Militerni R, & Bravaccio C (2010). Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. Journal of pediatric gastroenterology and nutrition, 51 (4), 418-24 PMID: 20683204